Tetrahydroimidazopyridine derivatives and salts thereof

ABSTRACT

Tetrahydroimidazopyridine derivatives which are useful for the treatment of irritable bowel syndrome are provided and can be represented by the following formula, ##STR1## wherein either one of X and Y is nitrogen and the other one is a radical represented by the formula ═C(R 1 )--; and R is a radical of the formula ##STR2## a radical of the formula ##STR3## or a radical of the formula ##STR4## in which R 1 , R 2  and R 3  are same or different and represent hydrogen or a C 1  -C 6  alkyl group, and salts thereof. Pharmaceutical compositions are also provided.

FIELD OF THE INVENTION

This invention relates to tetrahydroimidazopyridine derivatives andsalts thereof which are useful as medicines.

The compounds of this invention and salts thereof are considered to beuseful for the prevention and treatment of the syndrome ofhypersensitive intestinal diseases (irritable bowel syndrome) and thelike.

BACKGROUND TECHNIQUES

As a result of intensive studies on the compounds having the antagonismagainst 5-HT₃ receptor, tile present inventors discovered that thecompounds represented by the above-mentioned general formula are novelcompounds having a high degree of antagonism against 5-HT₃ receptor, andaccomplished this invention on the basis of these findings.

DISCLOSURE OF THE INVENTION

The term "lower" described in this specification means, unless otherwisespecified, a linear or branched carbon chain having a carbon number of 1to 6. Accordingly, as examples of the "lower alkyl group" may bementioned methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertbutyl,pentyl, isopentyl, hexyl, 1 -methylpentyl, 2-methylpentyl and2-ethylbutyl groups. Of these, the groups having a carbon number of 1 to3, such as methyl, ethyl and propyl groups are the most preferable.

In addition, some of the compounds of this invention can form salts, andthis invention also includes the salts of the compounds represented bythe above-mentioned general formula (I). As examples of these salts, maybe mentioned salts with an inorganic base (such as sodium andpotassium), salts with an organic base (such as ethylamine, propylamine,diethylamine, triethylamine, morpholine, piperidine, N-ethylpiperidine,diethanolamine and cyclohexylamine), salts with a basic amino acid (suchas lysine and ornithine), ammonium salts, salts with a mineral acid(such as hydrochloric, sulfuric, phosphoric and hydrobromic acids),salts with an organic acid (such as acetic, oxalic, succinic, citric,maleic, malic, fumaric, tartaric and methanesulfonic acids), and saltswith an acidic amino acid (such as glutamic and aspattic acids).

Furthermore, the compounds of this invention contain an asymmetriccarbon atom in the molecule, and the compounds represented by thegeneral formula (I) include all kinds of isomers based on thisasymmetric atom, such as optically active compounds, rasemic compoundsand diastereomers.

Preparative Methods

Described below are the typical preparative methods for the compounds ofthis invention. ##STR5##

The compounds of this invention represented by the general formula (Ia)or (Ib) can be obtained by the reaction of an aniline derivativerepresented by the general formula (II), or 2,3-dihydroindolerepresented by the formula (III), with a carboxylic acid represented bythe general formula (Iv) or a reactive derivative thereof.

This reaction is an amide-forming reaction, and hence a variety ofwell-known methods may be applicable. There is no specific limitationupon the kind of solvent to be used, insofar as it is inert to thereaction. As Examples of the solvent to be used, may be mentioneddioxane, diethyl ether, tetrahydrofuran, chloroform, ethyl acetate anddiemtylformamide, etc.

The compound (Iv) may be directly used for the reaction with thecompound (II) or the compound (III), or may be used for that reaction inthe form of a reactive, carboxy derivative in some cases.

When the compound (IV) itself is used for the reaction, any condensationagent commonly employed may be applicable (such asN,N-dicyclohexylcarbodiimide).

As examples of the reactive, carboxy derivative of compound (IV), may bementioned acid halides, acid anhydride, acid azide, and various activeesters employed for peptide synthesis.

The reaction should preferably be carried out in the presence of a basein some cases, depending on the type of the reactive derivative ofcompound (IV) used. As examples of the base used in this case, may bementioned inorganic bases (such as sodium bicarbonate, potassiumbicarbonate, sodium carbonate and potassium carbonate) and organic bases(such as triethylamine, diisopropylethylamine, dimethylaniline andpyridine).

The compound (II) or compound (III) is generally used for the reactionin this form, but may also be used, as required, in the form of analakali metal salt for the reaction with the reactive derivative ofcompound (IV).

The amount of compound (II) or (III) to be used for the reaction shouldpreferably be at least equimolar to the amount of compound (IV) or itsreactive derivative.

The reaction may be carried out under cooling, at room temperature orunder heating depending on the type of amide formation reaction adopted,but is generally carried out under cooling or at room temperature.##STR6##

The compounds of this invention represented by the general formula (Ic)can be obtained by the reaction of a compound represented by the generalformula (V) with a carboxylic acid represented by the general formula(IV) or a reactive derivative thereof.

This is a reaction for the synthesis of carbonyl compounds using acarboxylic acid or a derivative thereof, and hence a variety ofwell-known methods are applicable.

When a carboxylic acid compound (IV) itself is used, dehydrocondensationreaction with a compound (V) is adopted, in which polyphosphoric acid,for example, is used as the condensation agent. This reaction may becarried out in the absence of solvent, or may also be carried out byusing a solvent, wherein there is no specific limitation upon the kindof solvent to be used insofar as it is inert to the reaction. Ingeneral, a solvent having a proper boiling point is used, with thereaction temperature being taken into consideration. As examples of thesolvent to be used, may be mentioned decalin, tetralin and diglyme, andthe reaction is carried out at room temperature or preferably underheating.

When an acid halide of compound (IV) is used, Friedel-Crafts acylationreaction is adopted. This is a well-known reaction including manyvariations. In this case, is used a Lewis acid as catalyst, such asaluminum chloride, ferric chloride, tin chloride, trifluoroboricacid-diethyl ether complex and titanium tetrachloride. Any kind ofsolvent may be used insofar as it is inert to the reaction, but apreferable one should be selected depending on the type of Lewis acidused (such as acetonitrile and carbon disulfide). The reaction iscarried out at room temperature or preferably under heating.

When an acid amide of compound (IV) is used, Vilsmeyer reaction isadopted. This is also a well-known reaction frequently employed for thesynthesis of heterocyclic carbonyl compounds. As the reagent forconverting the amide into Vilsmeyer complex, may be generally used anordinary halogenating agent, such as phosphorus pentachloride andphosphorus oxychloride. This reaction may be carried out in the absenceof solvent, or may also be carried out by using a solvent, wherein thereis no specific limitation upon the kind of solvent to be used insofar asit is inert to the reaction. As a typical example of the solvent, may bementioned 1,2-dichloroethane.

The reaction is carried out at room temperature or preferably underheating. ##STR7##

This is an N alkylation reaction, and a variety of well-known methodsmay be applicable.

As an example of N-alkylation, may be mentioned direct N-alkylationusing an alkylating agent. In this case, the reaction may be carried outunder cooling, at room temperature or under heating, but is preferablycarried out under cooling or at room temperature. There is no specificimitation upon the kind of solvent to be used insofar it is inert to thereaction. As examples of proper solvent, may be mentioned dioxane anddimethylformamide. The reaction is carried out in the presence of abase, or the amino group in the compound (VI) is previously convertedinto an alkali metal salt and then subjected to N-alkylation reaction.

As examples of the alkylating agent, may be mentioned alkyl halides andalkyl sulfates. As examples of the base, may be mentioned inorganicbases (such as sodium bicarbonate, potassium bicarbonate, sodiumcarbonate and potassium carbonate), and organic bases (such astriethylamine, diisopropylamine, dimethylaniline and pyridine).

The compounds of this invention thus prepared are isolated and purifiedin the free form or as salts thereof. The isolation and purification areperformed through oridinary chemical operations, such as extraction,crystallization, recrystallization and various types of chromatography.

Racemic compounds can be converted into pure stereoisomers by using aproper starting compound or by the ordinary racemic resolution methodfor example, a method of conversion into the diastereomer salt with anoptically active salt (e.g., tartaric acid) followed by opticalresolution).

Effects Achieved by the Invention

The compounds of this invention and salts thereof specifically preventedthe temporary, slow pulse in anesthetized rats caused by serotonin, andare therefore considered to have antagonism against 5-HT₃. Accordinglythe compounds of this invention are considerd be effective forpreventing the irritable bowel syndrome and the like,

The pharmacological effects of the compounds of this invention weredemonstrated by the methods described below.

1) Antagonism against 5-HT₃ Receptor

A male Wistar rat nine weeks old was anesthetized by intraperitonealadministration of 1 g/Kg urethane, and the blood pressure and heart ratewere measured while practicing artificial respiration. The temporarydecrease in the heart rate and the fall of blood pressure caused byintravenous administration of serotonin, or 2-methylserotonin which is aselective agonist against 5-HT₃, were recognized as the index of areaction through the 5-HT₃ receptor [Bezold-Jarish Reflex; Paintal, A.S. Physiol. Rev., 53, 159 (1973)]

A compound of this invention or a salt thereof, if administeredintravenously (0.03 to 3 μg/Kg) 10 minutes before the administration ofserotonin or 2-methylserotonin, or administered orally (1 to 30 μg/Kg)60 minutes before, prevented the decrease in the heart rate and the fallof blood pressure caused by serotonin or 2-methylserotonin in a degreedepending on the dosage.

2) Prevention of Vomit Caused by Carcinostatic Agents

3) Prevention of Stress Feces Excretion

A male Wistar rat nine weeks old was put in a restrictive cage, and thenumber of excreted feces was measured. A compound of this invention or asalt thereof, if administered intravenously (1 to 100 μg/Kg), preventedthe acceleration of defecation caused by the restrictive stress in adegree depending on the dosage.

In addition, tile compounds of this invention are low in toxicity.

Pharmaceutical preparations containing, as active ingredient, one or twokinds or more kinds of the compounds of this invention or salts thereof(tablets, powders, beadlets, capsules, pills, solutions, injections,suppositories, ointments and adhesive plasters, etc.) are prepared bythe use of a carrier, an excipient and other additives commonlyemployed, and are administered orally (including sublingualadministration) or parenterally.

As the carrier and excipient for pharmaceutical manufacturing, are usedsolid or liquid, nonpoisonous materials. As examples of such materials,may be mentioned lactose, magnesium stearate, starch, talc, gelatin,agar, pectin, gum arabic, olive oil, sesame oil, cacao butter, ethyleneglycol and other materials commonly employed.

The clinical dosage of the compounds of this invention is properlydetermined by taking the illness conditions, the body weight, the age,the sex distinction and other factors of the patient being treated, butthe proper daily dosage for adults is generally 0.1 to 10 mg forintravenous injection and 0.5 to 50 mg for oral administration, which isadministered all at once or is subdivided in several doses.

EXAMPLES

The following Examples will further illustrate the invention. Inaddition, the preparative methods of the starting materials used inthese Examples are described in Reference Examples.

REFERENCE EXAMPLE 1 A. Sulfate of methylimidazo[1,5-a]pyridin-6-yl-carboxylate ##STR8##

Sodium acetate (4.77 g) and hydroxylamine hydrochloride (4.04 g) wereadded to 30 ml methanol, and the mixture was stirred at room temperaturefor 30 minutes. The salts thus formed were removed by filtration, 3.20 gof methyl 6-formylnicotinate was added to the filtrate, and the mixturewas stirred overnight at room temperature. After distilling off thesolvent from the reaction mixture under reduced pressure, an aqueoussolution of potassium carbonate was added, and the resulting mixture wasextracted with a mixture of chloroform and isopropanol. The organiclayer collected was dried over anhydrous magnesium sulfate, and thesolvents were distilled off from the dried solution under reducedpressure, thus giving 3.21 g of methyl 6-hydroxyiminonicotinate as solidproduct.

Physicochemical Properties

(i) NMR spectrum (CDCl-CD₃ OD) δ: 4.00 (s, 3H), 7.95 (d, 1H), 8.20 (s,1H), 8.35 (dd, 1H), 9.15 (d, 1H)

(ii) Mass spectrum (EI): m/z 180(M⁺) ##STR9##

The compound obtained in (1) above (3.16 g) was added to a mixture of 34ml water and 51 ml acetic acid, and 5.73 g of zinc powder was thenslowly added under ice-water cooling. The mixture was stirred for 30minutes, the insoluble matters were filtered off by using Celite, thefiltrate was concentrated to dryness under reduced pressure, an aqueoussolution of sodium carbonate was added to the residue, and the mixturewas extracted with chloroform. The organic layer collected was driedover anhydrous magnesium sulfate, and the solvent was distilled off fromthe dried solution under reduced pressure, thus giving 2.90 g of oilymethyl 6-aminomethylnicotinate.

Physicochemical Properties

(i) NMR spectrum (CDCl₃) δ: 3.95 (s, 3H), 4.05 (s, 2H), 7.35 (d, 1H),8.25 (dd, 1H), 9.15 (d, 1H)

(ii) Mass spectrum (EI): m/z 166(M⁺) ##STR10##

The compound obtained in (2) above (2.80 g) was added to 20 ml formicacid, and the mixture was stirred overnight at 100° C. and thenconcentrated to dryness under reduced pressure. An aqueous solution ofsodium carbonate was added to the residue, the mixture was extractedwith chlororform, the organic layer collected was dried over anhydrousmagnesium sulfate, and the solvent was distilled off from the driedsolution under reduced pressure. The residue was washed with diethylether, thus giving 2.07 g of methyl 6-formylaminomethylnicotinate assolid product.

Physicochemical Properties

(i) NMR spectrum (CDCl₃) δ: 3.95 (s, 3H), 4.65 (d, 2H), 7.30 (d, 1H),8.25 (dd, 1H), 8.35 (s, 1H), 9.15 (d, 1H)

(ii) Mass spectrum (EI): m/z 194(M⁺) ##STR11##

The compound obtained in (3) above (2.05 g) was added to 15 mldichloroethane, 2.0 ml of phosphorus oxychloride was then added, and themixture was heated under reflux for one hour, The reaction mixture wasconcentrated under reduced pressure, an aquous solution of sodiumbicarbonate was added to the concentrate, and the mixture was extractedwith chloroform. The organic layer collected was dried over anhydrousmagnesium sulfate, the solvent was distilled off from the dried solutionunder reduced pressure, and the residue was washed with diethyl ether,thus giving 1.79 g of methyl imidazo[1,5-a]pyridine-6-carboxylate.

Physicochemical Properties

(i) NMR spectrum (CDCl₃) δ: 3.94 (s, 3H), 7.20 (dd, 1H), 7.45 (d, 1H),7.46 (s, 1H), 8.22 (s, 1H), 8.74 (d, 1H)

(ii) Mass spectrum (EI): m/z 176(M⁺)

This compound was then treated with equimolar sulfuric acid in ethanol,thus giving 2.51 g of sulfate of methylimidazo[1,5-a]pyridin-6-yl-carboxylate.

Physicochemical Properties

(i) Elemental analysis (as C₉ H₈ N₂ O₂ ·H₂ SO₄)

    ______________________________________                                                C(%)  H(%)        N(%)    S(%)                                        ______________________________________                                        Calcd.    39.42   3.68        10.21 11.69                                     Obsd.     39.71   3.59         9.99 11.51                                     ______________________________________                                    

(ii) NMR spectrum(DMSO-d₆) δ: 3.90 (s, 3H), 7.45 (dd, 1H), 7.90 (s, 1H),8.05 (s, 1H), 9.30 (d, 1H), 9.55 (s, 1H)

(iii) Mass spectrum (EI): m/z 176(M⁺, in the free from)

B. Methyl 5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-6-carboxylate##STR12##

The sulfate of methyl imidazo[1,5-a]pyridine-6-carboxylate obtained in Aabove (2.19 g), 5% paradium-carbon(0.7 g) and acetic acid (30 ml) wereput in a 100-ml autoclave, and the mixture was stirred overnight at 70°C. under a hydrogen gas pressure of 65 atmospheres. The insolublematters were filtered off from the reaction mixture by using Cerite, thefiltrate was concentrated to dryness under reduced pressure, an aqueoussolution of sodium carbonate was added to the residue, and the resultingmixture was extracted with chloroform. The organic layer collected wasdried over anhydrous magnesium sulfate, and the solvent was distilledoff from the dried solution under reduced pressure, thus giving 1.4 g ofmethyl 5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-6-carboxylate as solidproduct.

Physicochemical Properties

(i) NMR spectrum (CDCl₃) δ: 1.70-2.10 (m, 1H). 2.10-2.40 (m, 1H),2.50-3.10 (m, 3H), 3.70 (s, 3H), 3.95-4.40 (m, 2H), 6.75 (bs, 1H), 7.40(bs, 1H)

(ii) Mass spectrum (EI): m/z 180(M⁺)

C. Hydrochloride of5,6,7,8-tetrahydroimidazo[1,5-a]-pyridine-6-carboxylic acid ##STR13##

A mixture of the compound obtained in B above (1.4 g), 15 ml water and 5ml concentrated hydrochloric acid was stirred overnight at 100° C., thereaction mixture was concentrated to dryness under reduced pressure, andthe residue was washed with acetone, thus giving 1.35 g of hydrochlorideof 5,6,7,8-tetrahydroimidazo[1,5-a ]pyridin-6-carboxylic acid as solidproduct.

Physicochemical Properties

(i) NMR spectrum (DMSO-d₆) δ: 1.9-2.3 (m, 2H), 2.75-3.0 (m, 2H), 3.0-3.3(m, 1H), 4.1-4.6 (m, 2H), 7.4 (s, 1H), 9.1 (s, 1H

(ii) Mass spectrum (EI): m/z 166(M⁺ in the free form)

REFERENCE EXAMPLE 2 Synthesis of hydrochloride of1-methyl-5,6,7,8-tetrahydroimidazo[1,5-a ]pyridine-7-carboxylic acid A.Ethyl 1-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-7-carboxylate##STR14##

Ethyl 4-chlorobutyrate (7.0 g) was added at room temperature to asolution of 5-methyl-4-imidazole-carbaldehyde (4.17 g) and 60% oilysodium hydride (2.0 g) in 50 ml dimethylformamide (prepared by stirringat 50° C. for one hour). The resulting mixture was heated at 70° C. forfour hours and then concentrated to dryness under reduced ressure, waterwas added to the residue, and the mixture was extracted with ethylacetate. The organic layer collected was washed with water and then withsaturated aqueous solution of sodium chloride, and dried over anhydrousmagnesium sulfate. The dried solution was concentrated to dryness underreduced pressure, and the residue was subjected to column chromatographyon silica gel (80 g). Elution with ethyl acetate gave 2.35 g (28%) of anabout 1:1 mixture of1-(3-ethoxycarbonylpropyl)-5-methyl-4-imidazole-carbaldehyde and1-(3-ethoxylcarbonylpropyl)-4-methyl-5-imidazole-carbaldehyde.

Physicochemical Properties

(i) NMR Spectrum(CDCl₃) δ: 1.25 (3H, t, J=7Hz), 1.85-2.70 (4H, m), 2.49,2.52 (3H for all, s for each), 3.80-4.50 (4H, m), 7.40, 7.48 (1H forall, s for each), 9.71, 9.80 (1H for all, s for each)

60% Oily sodium hydrice (0.45 g) was added to a mixture comprising 2.23g of the mixture of 1-(3-ethoxycarbonypropyl)-5-methyl-4-imidazole-carbaldehyde and1-(3-ethoxycarbonylpropyl)-4-methyl-5-imidazole-carbaldehyde obtainedabove, 3 g of molecular sieves (4A) and 30 ml toluene at a temperatureof 110° C., and the resulting mixture was stirred at the sametemperature for six hours. The reaction mixture was filtered, thefiltrate was concentrated to dryness under reduced pressure, the residuewas subjected to column chromatography on silica gel (30 g), and elutionwith ethyl acetate gave 0.85 g of ethyl1-methyl-5,6-dihydroimidazo[1,5-a ]pyridine-7-carboxylate.

Physicochemical Properties

(i) NMR spectrum (CDCl₃) δ: 1.34 (3H, t, J=7Hz), 2.32 (3H, s), 2.53-3.01(2H, m), 3.85-4.50 (4H, m), 7.40 (1H, s), 7.48 (1H, s)

(ii) Mass spectrum (EI): m/z 206(M⁺) ##STR15##

Ethyl 1-methyl-5,6-dihydroimidazo[1,5-a]pyridine-7-carboxylate (0.90 g)was subjected to catalytic reduction in 30 ml methanol at roomtemperature for ten hours by using 0.02 g of 5% paradium-carbon as thecatalyst. The reaction mixture was filtered, the filtrate wasconcentrated to dryness under reduced pressure, ethyl acetate was addedto the residue, and the resulting mixture was extracted with 0.5N-HCl.The aqueous layer collected was alkalized by addition of potassiumcarbonate and then extracted with dichloromethane, the organic layercollected was washed with saturated aqueous solution of sodium chloride,dried over anhydrous sodium sulfate and concentrated under reducedpressure, thus giving 0.89 g (98 %) of ethyl1-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-7-carboxylate.

Physicochemical Properties

(i) NMR spectrum (CDCl₃) δ: 1.30 (3H, t, J=7Hz), 1.70-2.30 (5H, m), 2.15(3H, s), 3.63-4.60 (4H, m), 7.25 (1H, s)

(ii) Mass spectrum (EI): m/z 208 (M⁺)

B. Hydrochloride of 1-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-7-carboxylic acid ##STR16##

Hydrochloride of1-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]-pyridine-7-carboxylic acid wasobtained in the same manner as in C of Reference Example 1 by using thecompound obtained in A above.

Physicochemical Properties

(i) NMR spectrum (DMSO-d₆) δ: 1.65-2.65 (2H, m), 2.22 (3H, s), 2.65-3.33(3H, m), 3.90-4.62 (2H, m), 8.98 (1H, s)

(ii) Mass spectrum (EI): 180(M⁺, in the free form)

REFERENCE EXAMPLE 3 Ethyl5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-7-carboxylate ##STR17##

Ethyl 5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-7-carboxylate wasobtained in the same manner as in A and B of Reference Example 2 byusing 2-imidazole-carbaldehyde as the starting material.

Physicochemical Properties

(i) NMR spectrum(CDCl₃) δ: 1.30 (3H, t, J=7Hz), 1.80-2.60 (2H, m),2.62-3.30 (3H, m), 3.80-4.55 (4H, m), 6.65-7.15 (2H, m)

(ii) Mass spectrum (EI): m/z 194(M⁺)

REFERENCE EXAMPLE 4 Hydrochloride of5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-6-carboxylic acid A. Sulfate ofMethyl Imidazo[1,2-a]Pyridine-6-Carboxylate ##STR18##

A solution of 12.5 g bromoacetaldehyde diethyl acetal in hydrochloricacid (prepared from 1.5 mg conc. HCl and 70 ml water) was stirred at 90°C. for 90 minutes, 3.30 g of methyl 6-aminonicotinate and 5 g of sodiumbicarbonate were then added at room temperature, and the resultingmixture was heated at 60° C. for 30 minutes. The reaction mixture wascooled to room temperature, alkalized by addition of potassium carbonateand extracted with ethyl acetate. The organic layer collected was washedwith saturated aqueous solution of sodium chloride, dried over anhydrousmagnesium sulfate and concentrated to dryness under reduced pressure,the residue was dissolved in ethanol, concentrated sulfuric acid wasadded to the ethanolic solution, and the crystals thus formed werecollected by filtration, thus giving 4.45 g (75 %) of sulfate of methylimidazo[1,2-a]pyridine-6-carboxylate.

Physicochemical Properties

(i) NMR spectrum (DMSO-d₆)

δ: 3.98 (3H, s), 8.09-8.44 (3H, m), 8.50 (1H, d, J=2 Hz), 9.66 (1H, d,J=1 Hz)

(ii) Mass spectrum (EI): m/z 176(M⁺, in the free form)

B. Methyl 5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-6-carboxylate##STR19##

Methyl 5,6,7,8-[etrahydroimidazo[1,2-a]pyridine-6-carboxylate wasobtained in the same manner as in B of Reference Example 1 by using thecompound obtained in A above.

Physicochemical Properties

(i) NMR spectrum(CDCl₃) δ: 1.80-2.65 (2H, m), 2.76-3.35 (3H, m), 3.77(3H, s), 4.18 (2H, d, J=7 Hz), 6.80 (1H, d, J=1 Hz), 6.98 (1H, d, J=1Hz)

(ii) Mass spectrum (EI): m/z 180(M⁺)

C. Hydrochloride of5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-6-carboxylic acid ##STR20##

Hydrochloride of 5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-6-carboxylicacid was obtained in the same manner as in C of Reference Example 1 byusing the compound obtained in B above.

Physicochemical Properties

(i) NMR spectrum (DMSO d₆) δ: 1.75-2.60 (2H, m), 2.80-3.45 (3H, m),3.95-4.65 (2H, m), 7.58 (1H, d, J=2 Hz), 7.64 (1H, d, J=2 Hz)

(ii) Mass spectrum (EI): 166(M⁺, in the free form)

EXAMPLE 1 ##STR21## Fumarate ofN-(2-Methoxyphenyl)-5,6,7,8-Tetrahydroimidazo[1,5-a]Pyridine-6-Carboxamide

To 5 ml of acetonitrile, were added 0.30 g of5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-6-carboxylic acid hydrochlorideand 0.22 ml of thionyl chloride, and the mixture was stirred at 60° C.for 30 minutes. The reaction mixture was concentrated to dryness underreduced pressure, 5 ml of acetonitrile was added to the residue, and0.74 g of 2-anisidine was then added under ice-water cooling. Theresulting mixture was stirred overnight at room temperature andconcentrated to dryness under reduced pressure, water was added to theresidue, and the pH was adjusted to about 4 by addition of dilutehydrochloric acid. This solution was washed with diethyl ether, and thepH was adjusted to about 9 by addition of potassium carbonate. Theresulting solution was extracted with chloroform, the organic layercollected was dried over anhydrous magnesium sulfate, and the solventwas distilled off from the dried solution under reduced pressure. Theresidue was washed with diethyl ether, an equimolar amount of fumaricacid was added, and the mixture was recrystallized with methanol, thusgiving 0.29 g of fumarate ofN-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-6-carboxamidehaving a melting point of 188°-189° C.

Physicochemical Properties

(i) Elemental analysis (as C.sub. 15H₁₇ N₃ O₂ ·C₄ H₄ O₄ ·0.1CH₃OH·0.45H₂ O)

    ______________________________________                                               C(%)        H(%)    N(%)                                               ______________________________________                                        Calcd.   57.54         5.64    10.54                                          Obsd.    57.82         5.47    10.24                                          ______________________________________                                    

(ii) Mass spectrum (EI): m/z 271(M⁺, in the free from)

The following compounds were obtained in the same manner as in Example1.

EXAMPLE 2 ##STR22##6-[(2,3-Dihydroindol-1-yl)carbonyl]-5,6,7,8-tetrahydroimadazo[1,5a]pyridine·0.5fumarate Physicochemical Properties

(i) Melting point: 206°-207° C. (methanol)

(ii) Elemental analysis (as C₁₆ H₁₇ N₃ O·0.5C₄ H₄ O₄)

    ______________________________________                                               C(%)        H(%)    N(%)                                               ______________________________________                                        Calcd.   66.45         5.89    12.91                                          Obsd.    66.13         5.84    12.70                                          ______________________________________                                    

(iii) Mass spectrum (HI): m/z 267(M⁺, in the free form)

EXAMPLE 3 ##STR23##N-(o-Methoxyphenyl)-1-methyl-5,6,7,8-tetrahydroimidazo[1.5-a]pyridine-7-carboxamide·1.5fumaratePhysicochemical Properties

(i) Melting point: 192°-194° C. (methanol-acetonitrile)

(ii) Elemental analysis (as C₁₆ H₁₉ N₃ O₂ ·1.5C₄ H₄ O₄)

    ______________________________________                                               C(%)        H(%)    N(%)                                               ______________________________________                                        Calcd.   57.51         5.48    9.15                                           Obsd.    57.61         5.55    9.45                                           ______________________________________                                    

(iii) Mass spectrum (EI): 285(M⁺, in the free form)

EXAMPLE 4 ##STR24## 7-(2,3-dihydro1-Indolylcarbonyl)-1-methyl-5,67,8-tetrahydroimidazo[1,5-a]pyridine·1.5fumarate PhysicochemicalProperties

(i) Melting point: 192°-194° C. (methanol-acetonitrile)

(ii) Elemental analysis (as C₁₇ H₁₉ N₃ O·1.5C₄ H₄ O₄)

    ______________________________________                                               C(%)        H(%)    N(%)                                               ______________________________________                                        Calcd.   60.65         5.53    9.23                                           Obsd.    60.56         5.47    9.23                                           ______________________________________                                    

(iii) Mass spectrum (EI): 281(M⁺, in the free form)

EXAMPLE 5 ##STR25##N-(o-Methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]-pyridine-6-carboxamide·1.5fumaratePhysicochemical Properties

(i) Melting point: 181°-183° C. (methanol-acetonitrile)

(ii) Elemental analysis (as C₁₅ H₁₇ N₃ O₂ ·1.5C₄ H₄ O₄)

    ______________________________________                                               C(%)        H(%)    N(%)                                               ______________________________________                                        Calcd.   56.63         5.20    9.43                                           Obsd.    56.60         5.23    9.52                                           ______________________________________                                    

(iii) Mass spectrum (El): 271(M⁺, in the free form)

EXAMPLE 6 ##STR26##6-(2,3-dihydro1-Indolylcarbonyl)-5,6,7,8-tetrahydroimidazo[1,2-a]-pyridinePhysicochemical Properties

(i) Melting point: 178°-180° C. (dichloromethane-hexane)

(ii) Elemental analysis (as C₁₆ H₁₇ N₃ O)

    ______________________________________                                               C(%)        H(%)    N(%)                                               ______________________________________                                        Calcd.   71.89         6.41    15.72                                          Obsd.    71.80         6.47    15.62                                          ______________________________________                                    

(iii) Mass spectrum (EI): 267(M⁺)

EXAMPLE 7 ##STR27##6-[(1-Methylindol-3-yl)carbonyl]-5,6,7,8-tetrahydroimidazo[1.5-a]pyridine.multidot.fumarate

To 4 ml of acetonitrile, were added 0.41 g of hydrochloride of5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-6-carboxylic acid and 0.29 mlof thionyl chloride in that order, and the mixture was stirred at 80° C.for one hour and then concentrated to dryness under reduced pressure.The residue was suspended in 4 ml acetonitrile, this suspension wasadded to a suspension of 3.35 ml pyrrolidine in 4 ml acetonitrile at atemperature lower than 10° C., and the mixture was stirred at roomtemperature for one hour and then concentrated to dryness under reducedpressure. An aqueous solution of potassium carbonate was added to theresidue, the mixture was extracted with chloroform containing a smallamount of methanol, the organic layer collected was dried over anhydrousmagnesium sulfate, and the dried solution was concentrated to drynessunder reduced pressure (concentration after addition of toluene wasrepeated twice).

The residue was dissolved in ethanol, 0.5 ml of 4N-HCl solution in ethylacetate was added to the ethanolic solution, and the mixture wasconcentrated to dryness under reduced pressure.

Dichloroethane (3 ml) and 1-methylindole (0.23 g) were added to theresidue, 0.32 g of phosphorus oxychloride was then added, and themixture was stirred at 80° C. for four hours. The solvent was distilledoff from the reaction mixture under reduced pressure, an aqueoussolution of potassium carbonate was then added, and the mixture wasextracted with chloroform. The solvent was distilled off from thecollected organic layer under reduced pressure, the residue wassubjected to column chromatography (silica gel, chloroform-methanol),and the eluate was treated with a calculated amount of fumaric acid inmethanol, thus giving 0.08 g of6-[(1-methylindol-3-yl)carbonyl]-5,6,7,8-tetrahydroimidazo[1,5-a)pyridine.multidot.fumaratehaving a melting point of 183°-185° C.

Physicochemical Properties

(i) Elemental analysis (as C₁₇ H₁₇ N₃ O.C₄ H₄ O₄.0.3CH₃ OH)

    ______________________________________                                               C(%)        H(%)    N(%)                                               ______________________________________                                        Calcd.   63.17         5.52    10.37                                          Obsd.    62.97         5.44    10.35                                          ______________________________________                                    

(ii) Mass spectrum (EI): m/z 279(M⁺, in the free form)

EXAMPLE 8 ##STR28##N-(o-Methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-7-carboxamide.multidot.fumarate

A solution of 0.18 g ethyl5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-7-carboxylate in 10 ml of3N-HCl was heated overnight under reflux, the reaction mixture wasconcentrated to dryness under reduced pressure, and the residue wasdried, thus giving 0.18 g of5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-7-carboxylicacid·hydrochloride.

The mixture of this hydrochloride with 1 ml thionyl chloride was heatedat 60° C. for 20 minutes, the reaction mixture was again concentrated todryness, 3 ml of dichloromethane and 0.6 ml o-anisidine were added tothe residue in that order at room temperature, and the mixture wasstirred for one hour. After addition of dichloromethane, the reactionmixture was extracted with 0.5N-HCl, and the aqueous layer collected wasalkalized by adding potassium carbonate and extracted withdichloromethane. The organic layer collected was washed with saturatedaqueous solution of sodium chloride, dried over anhydrous sodium sulfateand concentrated to dryness under reduced pressure, and the residue wassubjected to chromatography on silica gel (10 g). Elution with 2%methanol-chloroform gave 0.11 g ofN-o-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-7-carboxamide,which was inverted into its fumarate by reaction with a calculatedamount of fumaric acid.

(i) Melting point: 151°-153° C. (methanol-acetonitrile)

(ii) Elemental analysis (as C₁₅ H₁₇ N₃ O₂ ·C₄ H₄ O₄)

    ______________________________________                                               C(%)        H(%)    N(%)                                               ______________________________________                                        Calcd.   58.91         5.46    10.85                                          Obsd.    59.01         5.47    11.21                                          ______________________________________                                    

(iii) Mass spectrum (EI): 271(M⁺, in the free form)

What is claimed is:
 1. Tetrahydroimidazopyridine derivative representedby the following formula, ##STR29## wherein either one of X and Y isnitrogen and the other one is a radical represented by the formula═C(R¹)--; and R is a radical of the formula ##STR30## a radical of theformula ##STR31## or a radical of the formula ##STR32## in which R¹, R²and R³ are same or different hydrogen atom or a lower alkyl group, andsalts thereof.
 2. Tetrahydroimidazopyridine derivative represented bythe following formula, ##STR33## wherein either one of X and Y isnitrogen atom and the other one is a radical represented by the formula═C(R¹)--; and R is a radical of the formula ##STR34## a radical of theformula ##STR35## or a radical of the formula ##STR36## in which R¹, R²and R³ are same or different and represent hydrogen or a C₁ -C₆ alkylgroup, and salts thereof.
 3. A compound according to claim 1 wherein Ris: ##STR37##
 4. A compound according to claim 1 wherein R is: ##STR38##5. A compound according to claim 1 wherein R¹, R² and R³ are selectedfrom the group consisting of hydrogen and C₁ -C₃ alkyl groups.
 6. Acompound according to claim 1 which is a member selected from the groupconsistingofN-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazol[1,5-a]pyridine-6-carboxamide6-[(2,3-dihydroindol-1-yl)carbonyl)-5,6,7,8-tetrahydroimidazol[1,5-a]pyridine;N-(o-methoxyphenyl)-1-methyl-5,6,7,8-tetrahydroimidazol[1,5-a]pyridine-7-carboxamide;7-(2,3-dihydro-1-indolylcarbonyl)-1-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridineN-(o-methoxyphenyl)-5,6,7,8-tetrahydroimidazol[1,2-a]-pyridine-6-carboxamide6-(2,3-dihydro1-indolylcarbonyl)-5,6,7,8-tetrahydroimidazol[1,2-a]-pyridine;6-[1-methylindol-3-yl)carbonyl]-5,6,7,8-tetrahydroimidazol[1,5-a]pyridine;andN-(o-methoxyphenyl)-5,6,7,8-tetrahydroimidazol[1,2-a]pyridin-7-carboxamide;orsalts thereof.
 7. A pharmaceutical composition containing a compoundaccording to claim 1 and pharmaceutically acceptable carrier.
 8. Apharmaceutical composition containing a compound according to claim 2and a pharmaceutically acceptable carrier.
 9. A pharmaceuticalcomposition containing a compound according to claim 3 and apharmaceutically acceptable carrier.